WO2022264109A1 - Multivalent influenza vaccines - Google Patents
Multivalent influenza vaccines Download PDFInfo
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- WO2022264109A1 WO2022264109A1 PCT/IB2022/055655 IB2022055655W WO2022264109A1 WO 2022264109 A1 WO2022264109 A1 WO 2022264109A1 IB 2022055655 W IB2022055655 W IB 2022055655W WO 2022264109 A1 WO2022264109 A1 WO 2022264109A1
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- WIPO (PCT)
- Prior art keywords
- mrna
- influenza
- vaccine composition
- lipid
- lnp
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Definitions
- the HA antigen and NA antigen is selected from the group consisting of H1N1, H3N2, H2N2, H5N1, H7N9, H7N7, H1N2, H9N2, H7N2, H7N3, H5N2, and H10N7 subtypes and/or B Yamagata and B/Victoria lineages.
- the LNP comprises between 1 and 20 mRNA molecules. In certain embodiments, the LNP comprises 5-10 or 6-8 mRNA molecules.
- the composition comprises eight LNPs, wherein each LNP comprises an mRNA encoding a different influenza antigen.
- FIG. 9B is a pair of graphs showing that Lipid A LNP formulations containing modified and unmodified CA09 HA mRNA were comparable as indicated by ELISA titers in mice.
- FIG. 17A shows the NAI titers are reported as Logio for serum samples taken at study days 0, 14, 28, 42, 56, 88, and 114.
- FIG. 17B shows the daily weight change after intranasal challenge on day 89 for single dose group and day 117 (89 days after second dose) for two dose group with 4LD50 of Belgium09 H1N1. Weights are presented as the percentage of weight lost from the day of challenge. Individual lines represent each animal.
- FIGs. 20A and 20B show T cell responses in NHP vaccinated with Sing 16 HA mRNA-LNP vaccine.
- T cells were determined by ELISPOT on day 42 in PBMC stimulated in vitro with peptide pools to represent the entire HA open reading frame.
- the responses of PBMC secreting IFN-g (FIG. 20A) or IL-13 (FIG. 20B) calculated as spots forming cells (SFC) per million PBMC are shown. Each symbol represents an individual sample, and the bar represent the geometric mean for the group.
- FIG. 31 depicts NAI titers for quadrivalent and octavalent mRNA-LNP vaccines, administered to mice for 4 different influenza strains.
- Scheme 1 General Synthetic Scheme for Lipids of Formulas (III), (IV), and (V)
- a cationic lipid at a molar ratio of 35% to 55% or 40% to 50% e.g., a cationic lipid at a molar ratio of 35%, 36%, 37%, 38%, 39%, 40%, 41% 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, or 55%;
- a cholesterol-based lipid at a molar ratio of 20% to 50%, 25% to 45%, or 28.5% to 43% e.g., a cholesterol-based lipid at a molar ratio of20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41% 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, or 50%); and
- the LNP may be multi-valent.
- the LNP may carry mRNAs that encode more than one influenza antigen, such as two, three, four, five, six, seven, or eight antigens.
- the LNP may carry multiple mRNA, each encoding a different influenza antigen; or carry a polycistronic mRNA that can be translated into more than one influenza antigen (e.g., each antigen-coding sequence is separated by a nucleotide linker encoding a self-cleaving peptide such as a 2A peptide).
- An LNP carrying different mRNA typically comprises (encapsulate) multiple copies of each mRNA.
- an LNP carrying or encapsulating two different mRNA typically carries multiple copies of each of the two different mRNA.
- the buffered solution preferably is isotonic and suitable for e.g., intramuscular or intradermal injection hi some embodiments, the buffered solution is a phosphate-buffered saline (PBS).
- PBS phosphate-buffered saline
- the mRNA disclosed herein may comprise a 5’ UTR that includes one or more elements that affect an mRNA’s stability or translation.
- a 5 ’ UTR may be about 10 to 5,000 nucleotides in length.
- a 5’ UTR may be about 50 to 500 nucleotides in length.
- the nucleic acid comprises at least one polyadenylation signal.
- the process of preparing mRNA-loaded UNPs includes a step of heating one or more of the solutions to a temperature greater than ambient temperature, the one or more solutions being the solution comprising the pre-formed lipid nanoparticles, the solution comprising the mRNA and the mixed solution comprising the UNP-encapsulated mRNA.
- the process includes the step of heating one or both of the mRNA solution and the pre-formed UNP solution, prior to the mixing step.
- the process includes heating one or more of the solutions comprising the pre formed UNPs, the solution comprising the mRNA and the solution comprising the UNP- encapsulated mRNA, during the mixing step.
- the majority of purified LNPs i.e., greater than about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% of the LNPs, have a size of about 70-150 nm (e.g., about 145 nm, about 140 nm, about 135 nm, about 130 nm, about 125 nm, about 120 nm, about 115 nm, about 110 nm, about 105 nm, about 100 nm, about 95 nm, about 90 nm, about 85 nm, or about 80 nm).
- nm e.g., about 145 nm, about 140 nm, about 135 nm, about 130 nm, about 125 nm, about 120 nm, about 115 nm, about 110 nm, about 105 nm, about 100 nm, about 95 nm, about 90
- Example 1 An exemplary, nonlimiting process for making an mRNA-FNP composition is described in Example 1. The process involves mixing of a buffered mRNA solution with a solution of lipids in ethanol in a controlled homogeneous manner, where the ratio of lipids:mRNA is maintained throughout the mixing process.
- the mRNA is presented in an aqueous buffer containing citric acid monohydrate, tri-sodium citrate dihydrate, and sodium chloride.
- the mRNA-LNP vaccines can be administered to subjects in need thereof in a prophylactically effective amount, i.e., an amount that provides sufficient immune protection against a target pathogen for a sufficient amount of time (e.g., one year, two years, five years, ten years, or life-time). Sufficient immune protection may be, for example, prevention or alleviation of symptoms associated with infections by the pathogen.
- a prophylactically effective amount i.e., an amount that provides sufficient immune protection against a target pathogen for a sufficient amount of time (e.g., one year, two years, five years, ten years, or life-time).
- Sufficient immune protection may be, for example, prevention or alleviation of symptoms associated with infections by the pathogen.
- multiple doses (e.g., two doses) of the vaccine are injected to subjects in need thereof to achieve the desired prophylactic effects.
- the composition offers cross-protection against multiple strains of influenza A Hl-subtype viruses (e.g., H1N1), influenza A H3-subtype viruses (e.g., H3N2), influenza A H5-subtype viruses (e.g., H5N1), and/or influenza B viruses (e.g., Yamagata lineage, Victoria lineage).
- influenza A Hl-subtype viruses e.g., H1N1
- influenza A H3-subtype viruses e.g., H3N2
- influenza A H5-subtype viruses e.g., H5N1
- influenza B viruses e.g., Yamagata lineage, Victoria lineage.
- the vector can be used to express mRNA in a host cell.
- the vector can be used as a template for IVT.
- the construction of optimally translated IVT mRNA suitable for therapeutic use is disclosed in detail in Sahin, et al. (2014). Nat. Rev. Drug Discov. 13, 759-780; Weissman (2015). Expert Rev. Vaccines 14, 265-281.
- Self-replicating RNA can be produced by using replication elements derived from, e.g., alphaviruses, and substituting the structural viral proteins with a nucleotide sequence encoding a protein of interest (e.g., influenza protein).
- a self-replicating RNA is typically a positive-strand molecule which can be directly translated after delivery to a cell, and this translation provides an RNA-dependent RNA polymerase which then produces both antisense and sense transcripts from the delivered RNA.
- the delivered RNA leads to the production of multiple daughter RNAs.
- each self-replicating RNA described herein encodes (i) an RNA- dependent RNA polymerase which can transcribe RNA from the self-replicating RNA molecule and (ii) an influenza protein antigen.
- the polymerase can be an alphavirus replicase, e.g., comprising one or more of alphavirus proteins nsPl, nsP2, nsP3, and nsP4. Whereas natural alphavirus genomes encode structural virion proteins in addition to the non-structural replicase polyprotein, in certain embodiments, the self-replicating RNA molecules do not encode alphavirus structural proteins.
- RNA purified according to this disclosure can be useful as a component in pharmaceutical compositions, for example, for use as a vaccine. These compositions will typically include RNA and a pharmaceutically acceptable carrier.
- a pharmaceutical composition of the present disclosure can also include one or more additional components such as small molecule immunopotentiators (e.g., TLR agonists).
- a pharmaceutical composition of the present disclosure can also include a delivery system for the RNA, such as a liposome, an oil-in-water emulsion, or a microparticle.
- the pharmaceutical composition comprises a lipid nanoparticle (LNP).
- the composition comprises an antigen-encoding nucleic acid molecule encapsulated within an LNP.
- hEPO protein was used as a surrogate to measure the potency of the LNPs to delivery mRNA in vivo.
- a single dose of hEPO mRNA (0.1 pg) formulated in LNPs derived from various combinations of the components was injected into mice intramuscularly (IM). Serum collected at 6 hours and 24 hours after administration was tested for hEPO levels using ELISA.
- MC3 formulation an industry benchmark, was used a reference for the calculation of fold-increase in hEPO expression (Angew, Chem lntEd. (2012) 51:8529-33).
- the level of hEPO expression seen for each LNP formulation indicated the formulation’s ability to deliver mRNA into cells.
- the initial formulations included 2-dioleoyl- sn-glycero-3-phosphoethanolamine (DOPE; helper lipid), DMG-PEG2000, and cholesterol at the molar ratio of cationic lipid: DMG-PEG2000: cholesterol: DOPE at 40: 1.5:28.5:30. These formulations were found to have robust potency when compared to MC3 formulations.
- Further formulations were tested. Optimized formulations Lipid A LNP and Lipid B LNP are shown in Table 1.
- the mRNA in these formulations can be modified or unmodified and may encode an antigen derived from influenza.
- mRNA-LNP was administered as two mRNAs co encapsulated or dosed separately as singly encapsulated mRNAs.
- Lor both approaches a total of 0.4 pg LNP formulation was injected into mice by intramuscular injection. The first injection was given at study day 0 and the second injection was given at study day 28.
- the data show that the vaccines elicited robust immune functional responses. There did not appear to be any difference between the two administration approaches. These data show that co encapsulation did not cause hindrance or interference between the two mRNAs.
- mRNA transcripts encoding for hEPO, PL, CA09 HA, Sing 16 HA, Mich 15 NA, and Sing 16 NA were synthesized by in vitro transcription employing RNA polymerase with a plasmid DNA template encoding the desired gene using unmodified nucleotides.
- the resulting purified precursor mRNA was reacted further via enzymatic addition of a 5 ’ cap structure (Cap 1) and a 3’ poly(A) tail of approximately 200 nucleotides in length as determined by gel electrophoresis and purified. All mRNA preparations were analyzed for purity, integrity, and percentage of Cap 1 before storage at -20°C.
- mRNA-LNP formulations were characterized for size by dynamic light scattering, percentage encapsulation and were stored at -80°C at lmg/mL until further use by dilution with suitable buffer.
- hEPO-LNPs and FF-LNPs were utilized to check level of expression of target protein in vivo.
- NHPs were bled for serum isolation while under anesthesia administered intramuscularly usinglO mg/kg ketamine/1 mg/kg acepromazine (days -4, 2, 7, 14, 28, 30, 35, 42, 56, 90, and 180).
- the volume of blood withdrawn did not exceed established guidelines with respect to percentage of body weight and animal’s physical condition.
- Blood was withdrawn from anesthetized NHPs using femoral venipuncture using a Vacutainer 21 ga x 1” blood collection needle or Abbott Butterfly 23 ga x 3 ⁇ 4” tubing attached to BD Vacutainer® SSTTM gel tubes. Serum was isolated by spinning the tubes at room temperature at a speed of 1200 x g for 10 minutes.
- HAI assays were performed using the Sing 16 H3N2 and the CA09 H1N1 virus stocks (BIOQUAL, Inc.). Sera were treated with receptor-destroying enzyme (RDE) by diluting one- part serum with three parts enzyme and incubated overnight in a 37°C water bath. Enzyme was inactivated by a 30-minute incubation period at 56°C followed by addition of six parts PBS for a final dilution of 1/10. HAI assays were performed in V-bottom 96-well plates using four hemagglutinating units (HAU) of virus and 0.5% turkey RBC. The reference serum for each strain was included as a positive control on every assay plate.
- RDE receptor-destroying enzyme
- AGCAU C AAGCAGGACAU CGUGGGAAUUA ACGAGUGGU CCGGUUACU CCGGGA
- Serum hEPO quantified by ELISA demonstrated maximum expression at 6 h with approximately 12-fold higher erythropoietin expressed with hEPO-LNP compared to hEPO-MC3 (FIG. 11, panel (c)). Both hEPO-LNP and hEPO-MC3 showed similar expression kinetics in NHPs, detectable from 6 hours to 72 hours (FIG. 11, panel (d)). The results confirmed the utility of the present LNP formulation for efficient delivery of mRNA for expression both in vitro and in vivo.
- rHA Recombinant HA
- rHA antigens of the same strain were used to evaluate the total IgG responses in ELIS As.
- HA-specific antibodies were detected in all groups after a single dose, but the titers peaked at day 42 after the second dose (FIG. 12).
- HAI hemagglutination inhibition
- mice in the vaccine group survived the challenge with no mortality, and some mild morbidity marked by transient weight loss of less than 5% (FIG. 16B). However, those in the diluent control group suffered significant and rapid weight loss which led to high mortality rate (90%) by day 9. These results demonstrated high efficacy of HA-based MRT formulations in a lethal mouse influenza challenge model.
- T cells have been shown effective in reducing viral load and limiting disease severity in animal models (Rimmelzwaan et al., Vaccine (2008) 26(4):D41-D44; Sridhar et al., Nat Med. (2013) 19(10): 1305-12; Sridhar et al., Front Immunol. (2016) 7: 195), we evaluated recall T cells in the NHPs vaccinated with 45, 135, 250 pg of Sing 16 HA-LNP or with 45 pg of recombinant HA.
- HAI titers to HI or H3, or NAI titers to N1 or N2 were compared between the monovalent formulations vs. bivalent or quadrivalent formulations (FIG. 23).
- LNP formulations for mRNA vaccines were prepared, designated Lipid C (containing cationic lipid GL-HEPES-E3-E10-DS-3-E18-1), Lipid D (containing cationic lipid GL-HEPES-E3-E12-DS-4-E10), and Lipid E (containing cationic lipid GL-HEPES-E3 -E 12- DS-3-E14).
- Human Erythropoietin (hEPO) mRNA was used as a test mRNA. Expression of hEPO was measured by ELISA from samples taken from mice injected with the LNPs. Samples were taken 6 hours, 24 hours, 48 hours, and 72 hours after injection. As show in FIG. 24, hEPO expression was consistently higher at all time points with LNP formulations Lipid A, Lipid B, Lipid C, Lipid D, and Lipid E, compared to a control LNP formulation containing cationic lipid MC3.
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